The long-term objective of this subproject is to further understanding of the roles of endogenous neuropeptides in the regulation of voluntary alcohol intake and preference. The proposed research will characterize the effects of administrations of the neuropeptides thyrotropin releasing hormone (TRH) and leptin on the intake and choice of ethanol solutions in laboratory rats. These effects will be characterized through a dose-response analysis of neuropeptide action on ethanol consumption, quantitative ethological analysis of effects of peptides on observed emitted behaviors, and measurement of peptides' abilities to produce conditioned taste preference and aversion. Further experiments will characterize the interactions of these 2 peptides with the known satiating effects of cholecystokinin octapeptide (CCK). The specific aim of the experimental designs is to examine direct actions of peptides in the regulation of alcohol intake and preference in rats, and to determine interaction of peptides in the satiation of alcohol consumption. Proposed experiments will test the hypothesis that TRH and leptin are functional signals of satiation in the negative feedback control of alcohol intake and preference. Female and male Wistar rats and rats bred selectively for high ethanol preference, Myers High Ethanol Preference (M-HEP) rats, will be motivated to consume alcohol solutions by periodic access to alcohol in an ad lib choice with water or water deprivation. Peptides and controls will be injected or infused peripherally across a range of doses, and dose combinations, and intakes of alcohol, food, and water, observed behaviors, and body weights, will be measured and analyzed with multi-factorial methods. Interactions of peptides will be determined by isobolographic analyses as either infra-, supra-, or dose-additive. Results will allow a conclusion on the hypothesis that TRH and leptin function normally to control alcohol consumption. Research results will provide new information on the functions and interactions of endogenous humoral factors in the control of alcohol intake and associated behaviors. The proposed experiments will also define the drinking responses and other behaviors of a recently-developed experimental model of alcohol preference, the M-HEP rat. This preclinical data will provide a scientific basis for design of optimal pharmacological, nutritional, and psychophysiological interventions to treat the human disorders of alcohol abuse and alcoholism.